Advanced Drug Delivery Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH, 44272, USA.
Department of Biomedical Sciences, Kent State University, Kent, OH, 44240, USA.
Drug Deliv Transl Res. 2023 Oct;13(10):2533-2549. doi: 10.1007/s13346-023-01336-5. Epub 2023 Apr 4.
Homeostatic imbalance involving progressive stimulation of osteoclast (OC) differentiation and function will lead to an increased risk of fragility fractures. In this regard, we investigated gallium acetylacetonate (GaAcAc) as a possible treatment for osteoclastic bone resorption. Further, the extent to which suitable delivery systems can enhance the therapeutic potential of GaAcAc was evaluated. GaAcAc solution (10-50 µg/mL) suppressed OC differentiation using murine monocytic RAW 264.7 or hematopoietic stem cells. Methylcellulose-based hydrogels were fabricated and characterized based on biocompatibility with bone cells, GaAcAc loading, and thermoresponsive behavior using storage (G') and loss (G″) moduli parameters. Compared to GaAcAc solution, hydrogels loaded with GaAcAc (GaMH) were more effective in suppressing OC differentiation and function. The number and extent of bone resorption pits from ex vivo studies were markedly reduced with GaMH treatment. Mechanistic assessment of GaMH efficacy showed superiority, compared to GaAcAc solution, in downregulating the expression of key markers involved in mediating OC differentiation (such as NFAT2, cFos, TRAF6, and TRAP) as well as in bone resorption by OCs (cathepsin K or CTSK). Additional studies (in vitro and in vivo) suggested that the performance of GaMH could be ascribed to controlled release of GaAcAc and the ability to achieve prolonged bio-retention after injection in BALB/c mice, which plausibly maximized the therapeutic impact of GaAcAc. Overall, the work demonstrated, for the first time, the therapeutic efficacy of GaAcAc and the therapeutic potential of GaMH delivery systems in osteoclastic bone resorption.
涉及破骨细胞（OC）分化和功能渐进性刺激的体内平衡失调将导致脆性骨折的风险增加。在这方面，我们研究了乙酰丙酮镓（GaAcAc）作为治疗破骨细胞骨吸收的一种可能方法。此外，还评估了合适的递送系统在多大程度上可以增强 GaAcAc 的治疗潜力。GaAcAc 溶液（10-50μg/mL）通过鼠单核细胞 RAW 264.7 或造血干细胞抑制 OC 分化。基于与骨细胞的生物相容性、GaAcAc 负载和使用存储（G'）和损耗（G"）模量参数的热响应行为，制备并表征了基于甲基纤维素的水凝胶。与 GaAcAc 溶液相比，负载 GaAcAc 的水凝胶（GaMH）在抑制 OC 分化和功能方面更有效。来自体外研究的骨吸收陷窝数量和程度明显减少，用 GaMH 处理。GaMH 功效的机制评估表明，与 GaAcAc 溶液相比，GaMH 在下调参与介导 OC 分化的关键标记物（如 NFAT2、cFos、TRAF6 和 TRAP）的表达以及 OC 骨吸收（组织蛋白酶 K 或 CTSK）方面具有优越性。进一步的研究（体外和体内）表明，GaMH 的性能可归因于 GaAcAc 的控制释放以及在 BALB/c 小鼠中注射后实现延长的生物保留能力，这合理地最大限度地提高了 GaAcAc 的治疗效果。总的来说，这项工作首次证明了 GaAcAc 的治疗效果和 GaMH 递送系统在破骨细胞骨吸收中的治疗潜力。
